The term "epilepsies" is a collective designation for a group of central nervous system disorders having in common the repeated occurrence of sudden and transitory episodes of abnormal phenomena of motor, convulsive, sensory, autonomic or psychic origin. The seizures are nearly always correlated with abnormal and excessive discharges in the brain, which can be recorded by an electroencephalogram.
Epilepsy is the most common neurological disorder. Epilepsy afflicts millions of people world wide, and it is more common in children than in adults. For the purposes of drug treatment, it is useful to classify patients according to the type of seizure the patient experiences. The generally accepted classification of epileptic seizure comprises partial seizures consisting of focal and local seizures, and generalized seizures consisting of convulsive or nonconvulsive seizures.
Partial seizures are classified further as simple partial seizures, complex partial seizures, and partial seizures secondarily generalized. Generalized seizures are classified further as absence seizures, atypical absence seizures, tonic-clonic and atonic seizures. The epilepsies are presented in The Pharmacological Basis of Therapeutics, 8th Ed., Goodman and Rall, editors. Pergamon Press publishers. Ch. 19.
The antiepileptic drug phenytoin and its alkali metal salts as represented by lithium, sodium and potassium, are known for treating epilepsies, as disclosed in Pharmaceutical Sciences, Remington, 18th Ed., Mack Publishing Co. 1990. pp. 1078. Therapeutically, phenytoin and its pharmaceutically acceptable salts are considered a drug of choice for the management of generalized tonic-clonic (grand mal) seizures, complex partial (temporal lobe psychomotor) seizures and simple partial (focal) seizures.
While phenytoin and its alkali salts are indicated for treating epilepsies, there are serious shortcomings associated with this drug. For example, phenytoin is poorly soluble in aqueous fluids, and this property makes it difficult to both provide and deliver it from a dosage form in a known dose over an extended time. For a dosage form that operates by osmotic imbibition, this poor solubility leads away from an osmotic dosage form and controlled delivery. The drug leads away as it lacks the required physical-chemical property needed to provide an osmotic gradient for imbibing fluid into the dosage form. Then too, since phenytoin is practically insoluble in an aqueous fluid, a high-loading dose must be housed in a dosage form that results in an unacceptably large dosage form and this precludes its oral use.
Prior to this invention, antiepileptic drugs were administered in conventional forms, such as a nonrate-controlling, dose-dumping capsule, or a nonrate-controlling, dose-dumping tablet, or by a dose-dumping capsule, and usually at multiple, repetitive dosing intervals. This prior-art mode of therapy lead to an initial high dose of drug in the blood, followed by a decreased dose of drug in the blood. The concentration differences in dosing patterns are related to the presence and absence of administered drug, which is a major disadvantage associated with conventional dosage forms. Conventional dosage forms and their mode of operation, including dose peaks and valleys, are discussed in Pharmaceutical Sciences, Remington, 18th Ed., 1990, Mack Publishing Co. pp. 1676-1686; The Pharmaceutical and Clinical Pharmacokinetics, 3rd Ed., 1984, Lea and Febiger, Philadelphia, pp. 1-28; and in U.S. Pat. Nos. 3,598,122 and 3,598,123, both issued to Zaffaroni.
The above presentation dictates of the critical need for a dosage form that overcomes the shortcomings of conventional dosage forms, including tablets, capsules, elixirs and suspensions. These conventional dosage forms and their accompanying peaks and valleys do not provide for dosage-regulating drug therapy over an extended period of time. The antiepileptic drugs as delivered by the prior art are dosed twice or thrice a day, which does not lend itself to controlled and sustained therapy. This prior-art pattern of drug administration speaks of the need for a dosage form that can administer the drug in a rate-controlled pattern over an extended time to provide constant therapy and thereby eliminate the peaks, valleys and multiple, uncontrolled dosing of the drug.
The prior art provides controlled-release dosage forms for administering a drug continuously over time. Representative of these dosage forms are disclosed in U.S. Pat. No. 4,327,725, issued to Cortese and Theeuwes; and in U.S. Pat. Nos. 4,612,008, 4,765,989 and 4,783,337, issued to Wong, Barclay, Deters and Theeuwes. The dosage forms disclosed in these patents provide a controlled release of drug over a prolonged time for constant drug therapy and they eliminate the need for multiple dosing of a drug. These dosage forms can deliver many drugs for their intended therapy, but there are certain drugs that are not readily delivered from these dosage forms. For example, the antiepileptic drug phenytoin is poorly soluble in aqueous fluids and this property, coupled with the dose needed for therapy, makes for difficult manufacturing, and the dosage form too large for acceptable therapy.
It is immediately apparent in light of the above presentation that an urgent need exists for a dosage form endowed with controlled-release delivery for administering the antiepileptic drug phenytoin for its therapy. The need exists for a dosage form for delivering phenytoin in a controlled-sustained therapeutically effective phenytoin dose for providing extended therapy. The need exists also for a therapeutic composition comprising a dose of phenytoin, and for a method for administering a dose of phenytoin to a patient. It will be appreciated by those versed in the antiepileptic-medicinal art that if the above are made available they would represent a major advancement in the therapy of epilepsies.